© ISO 2016 Infusion equipment for medical use — Part 6 Freeze drying closures for infusion bottles Matériel de perfusion à usage médical — Partie 6 Bouchons à lyophilisation pour flacons de perfusion[.]
INTERNATIONAL STANDARD ISO 85 6-6 Third edition 2016-12-01 Infusion equipment for medical use — Part 6: Freeze drying closures for infusion bottles Matériel de perfusion usage médical — Partie 6: Bouchons à lyophilisation pour flacons de perfusion Reference number ISO 8536-6:2016(E) I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n © ISO 2016 ISO 85 6-6: 01 6(E) COPYRIGHT PROTECTED DOCUMENT © ISO 2016, Published in Switzerland All rights reserved Unless otherwise specified, no part o f this publication may be reproduced or utilized otherwise in any form or by any means, electronic or mechanical, including photocopying, or posting on the internet or an intranet, without prior written permission Permission can be requested from either ISO at the address below or ISO’s member body in the country o f the requester ISO copyright o ffice Ch de Blandonnet • CP 401 CH-1214 Vernier, Geneva, Switzerland Tel +41 22 749 01 11 Fax +41 22 749 09 47 copyright@iso.org www.iso.org ii I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Page Contents iv Introduction v Scope Normative references Terms and definitions Shape and dimensions Designation Material Requirements 7.1 General 7.2.1 Hardness 7.2.2 Fragmentation (coring) 7.2.3 Spike penetration force 7.2.5 Resistance to ageing 7.2.6 Residual moisture 7.3 Chemical requirements 7.4 Biological requirements Labelling Annex A (normative) Determination of fragments Annex B (normative) Determination of spike penetration force Annex C (normative) Spike retention/sealability Annex D (normative) Closure piercing device Annex E (informative) Determination of residual moisture Bibliography Foreword 7.2 Phys ical requirements 7.2 S p ike p enetratio n/s ealab ility © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n iii ISO 85 6-6: 01 6(E) Foreword I SO (the I nternational O rganiz ation for Standardiz ation) is a worldwide federation of national s tandards bodies (ISO member bodies) The work o f preparing International Standards is normally carried out through ISO technical committees Each member body interested in a subject for which a technical committee has b een es tablished has the right to b e represented on that committee I nternational organi zation s , governmental and non- governmental, in liaison with I SO, al so take p ar t in the work ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters o f elec trotechnical s tandardi z ation T he procedures used to develop this cument and those intended for its fur ther maintenance are describ ed in the I SO/I E C D irec tives , Par t I n p ar ticu lar the different approval criteria needed for the di fferent types o f ISO documents should be noted This document was dra fted in accordance with the editorial ru les of the I SO/I E C D irec tives , Par t (see www iso org/direc tives) Attention is drawn to the possibility that some o f the elements o f this document may be the subject o f patent rights ISO shall not be held responsible for identi fying any or all such patent rights Details o f any patent rights identified during the development o f the document will be in the Introduction and/or on the I SO l is t of p atent declarations received (see www iso org/p atents) Any trade name used in this document is in formation given for the convenience o f users and does not cons titute an endors ement For an explanation on the meaning o f ISO specific terms and expressions related to formity assessment, as well as information about I SO ’s adherence to the World Trade O rganization ( WTO) principles in the Technical B arriers to Trade (TB T ) see the following URL: www.iso.org/iso/foreword html T he committee res p ons ible for this document is I S O/ TC 76 , processing equipment for medical and pharmaceutical use Transfusion, infusion and injection, and blood This third edition cancels and replaces the second edition (ISO 8536-6:2009), which has been technically revised A lis t of al l p ar ts in the I SO series can b e found on the I S O webs ite iv I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Introduction Freeze drying closures are put on the top o f in fusion bottles a fter filling, leaving su fficient openings for the sublimation process and vacuum At the end o f the drying process, they can be fully inserted into the glass container by hydraulic or mechanical means in the vacuum chamber Freeze drying closures can pick up water during shipping, storage, washing and steam sterilization cycles, which is di fficult to remove in a subsequent drying cycle As a consequence, the freeze drying closures are usually loaded with residual moisture Depending upon the mass o f the freeze-dried product and the degree o f its sensitivity to water, the residual moisture in the rubber material can spoil the freeze-dried preparation during storage These specific process requirements have been addressed in this document by speci fying relevant requirements for freeze drying closures including a test method on determination o f residual moisture Primary packaging components made o f elastomeric materials are an integral part o f medicinal products and thus the principles o f current Good Manu facturing Practices (cGMP) apply to the manufacturing of these components Principles o f cGMP are described in, for example, ISO 15378 or GMP Guidelines as published by the European Community and the United States o f America © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n v I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n INTERNATIONAL STANDARD ISO 85 6-6: 01 6(E) Infusion equipment for medical use — Part 6: Freeze drying closures for infusion bottles Scope T h i s c ument s p e ci fie s the sh ap e, d i men s ion s , materi a l, p er forma nce re qu i rements and lab el l i ng the typ e o f clo s u re fre e ze - d r yi ng for for i n fu s ion b o ttle s , a s de s c rib e d i n I S O -1 , th at i s u s e d i n ne c tion with the (or lyoph i l i z ation) o f d r ugs and biolo gic a l m ateria l s The dimensional requirements are not applicable to barrier-coated closures C lo s u re s s p e c i fie d i n th i s c ument a re i ntende d for s i ngle u s e on ly T he p o tenc y, pu r ity, s tab i l ity a nd s a fe ty o f a me d ic i n a l pro duc t du r i ng its m a nu fac tu re a nd s torage NO TE c a n s tro ngl y b e a ffe c te d b y the n atu re a nd p er fo r m a nce o f the pr i m a r y p ackagi ng T he Normative references fol lowi ng c u ments are re ferre d to i n the tex t i n s uch a way th at s ome or a l l o f thei r content s titute s re qu i rements o f th i s c u ment For date d re ference s , on ly the e d ition cite d appl ie s For u ndate d re ference s , the late s t e d ition o f the re ference d c ument (i nclud i ng a ny amend ments) appl ie s ISO 3302 (all parts), Rubber — Tolerances for products ISO 7619-1, Rubber, vulcanized or thermoplastic — Determination Durometer method (Shore hardness) of indentation hardness — Part 1: ISO 8536-1, Infusion equipment for medical use — Part 1: Infusion glass bottles ISO 8536-3, Infusion equipment for medical use — Part 3: Aluminium caps for infusion bottles ISO 8871-1, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 1: Extractables in aqueous autoclavates ISO 8871-4, Elastomeric parts for parenterals and for devices for pharmaceutical use — Part 4: Biological requirements and test methods Terms and definitions For the pu r p o s e s o f th i s c u ment, the fol lowi ng term s and defi n ition s apply ISO and IEC maintain terminological databases for use in standardization at the following addresses: — IEC Electropedia: available at http://www.electropedia.org/ — ISO Online browsing platform: available at http://www.iso.org/obp freeze- drying lyophilization d r yi ng pro ce s s de s igne d to sublimation and desorption © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n remove s olvents from b o th aque ou s and non- aque ou s s ys tem s by ISO 85 6-6: 01 6(E) 3.2 freeze drying closure clo s ure wh ich enable s the d r yi ng o f a fro z en pha rmaceutic a l prep aration i n a vac uum cha mb er Shape and dimensions The dimens io ns o f 4.1 general des ign o f a freeze freeze drying clo s ures s hall b e as given in Table Figure illustrates the drying clo s ure Dimensions in millimetres Key positioning element spacers T he to ta l height o f the NO TE manufacturer and user fre e z e d r yi n g clo s u re , h , m ay va r y a nd i s s ub j e c t to mutu a l agre ement b e twe en Figure — E xample to illustrate a freeze drying closure design Table — Dimensions of freeze drying closures Dimensions in millimetres Nominal a 4.2 d2 a h2 h3 h4 ±0,3 ±0,2 ±0,3 min 32 30,8 23,6 4,0 3,7 28 27,1 19,6 3,4 ,2 The value of d2 i s ap p l ie d i n th at a re a wh ich i s de fi ne d b y h3 I f no t o therwis e s p ecified, general dimens io nal to lerances s hall b e in acco rdance with I S O 3 (all parts) d1 size I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) I f spacers are located on the top o f the flange, they shall not interfere with the marks for the injection site The height o f the spacers shall not exceed 0,3 mm 4.3 On the top sur face, there may be marks or indentations 4.4 I f the flange o f the closure has a slight conical shape, the conicity shall be 0,8 mm max in relation to the diameter in order to facilitate production The tolerances o f the trimming edge o f the flange shall comply with the tolerances specified in Table for the diameter d1 The plug part shall provide slits, channels or other appropriate means in conjunction with protruding or positioning elements at the outer diameter, which enable insertion in a drying (halfway) 4.5 position during the sublimation process 4.6 The design o f the positioning elements to hold the freeze drying closure firmly in the sublimation position should not compromise the full insertion of the closure The design o f the flange part in conjunction with the plug design shall permit both the reconstitution o f the freeze-dried product with the appropriate solvent and the removal o f the dissolved product by 4.7 means of a piercing device When freeze drying closures are put in place for the lyophilization process and the container is exposed to transport processes, they should exhibit sufficient shock and vibration resistance that under regular processing conditions they not fall o ff nor become distorted 4.8 4.9 All edges o f the closure may be rounded Designation A freeze drying closure for in fusion bottles can be designated by the words “ freeze drying closure” followed by the number o f this document followed by the nominal size EXAMPLE A freeze drying closure for in fusion bottles o f nominal size 32 complying with the requirements laid down in this document is designated as follows: Freeze drying closure I SO 85 - - Material The elastomeric material used shall meet the requirements specified in Clause The elastomeric material shall withstand two sterilization cycles when autoclaving in saturated steam at (121 ± 2) °C for 30 without exceeding the specified limits and without the impairment o f its performance characteristics under the conditions of normal use In case of other sterilization methods, e.g irradiation, the suitability o f the material shall be evaluated With regard to the special requirement for low residual moisture, the drying process shall be included in the evaluation of the material’s performance characteristics (see also 7.2.5) Closures shall be made from the elastomeric formulation originally tested and approved by the enduser The closure manu facturer shall ensure the formance o f each delivery with the type sample and the compliance with previously agreed functional and compendium requirements NOTE It is current practice to pre fer elastomeric materials which use straight or halogenated butyl rubbers as a base polymer, since this class o f materials exhibits an excellent barrier function against water vapour and gas permeation © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Requirements 7.1 General The requirements specified in to 7.4 represent minimum requirements which refer to the condition o f the elastomeric closures on receipt by the user 7.2 7.2 Physical requirements Hardness The hardness agreed between manu facturer and user shall not di ffer from the nominal value by more than ±5 Shore A when tested in accordance with ISO 7619-1 on special test specimen Alternatively, the hardnes s can b e tes ted on the clos ures according to I SO 48 I f tes ted according to I S O 48 , the microhardness shall not di ffer by more than ±5 IRHD from the type sample 7.2 Fragmentation (coring) When tes ted for fragmentation in accordance with Annex A, not more than fragments of diameter equal to or greater than µm p er 10 piercings shal l b e obs er ved 7.2 Spike penetration force When tested for penetrability in accordance with Annex B , the force needed to p enetrate the clos ure shal l not exceed N , and the average value shal l b e les s than 75 N No clos ure shal l b e pushed into the b ottle during piercing 7.2 Spike penetration/sealability When tes ted in accordance with Annex C , complete p enetration shal l b e achieved (no clos ure shal l b e pushed into the b ottle) in al l cases and no s igns of leakage shal l app ear b etween the s pi ke and the clos ure for a p erio d h; nor shal l the s pi ke b e pu l led from the clos ure during this time p erio d 7.2 Resistance to ageing T he ma ximum time b etween the date of manufac ture and the pharmaceutical us e shou ld b e agreed up on b etween the manufac turer of the clos ures and the user T he clos ures shal l maintain their p erformance charac teris tics throughout the entire shel f l ife of the medicinal product which is tested as part o f the stability test by the user NO T E Agei ng dep end s up on the s torage and hand li ng cond ition s A gu ide to s torage of vu lc ani zed rubb er i s given in I S O 2 7.2 Residual moisture Up on reques t, the rubb er manufac turer shal l give a recommendation at what time and temp erature (time/temperature profile) the user can reduce residual moisture from freeze drying closures to end up with a pre-defined moisture level, as exposure to dry heat may damage the elastomeric material Res idual mois ture can b e determined in accordance with Annex E 7.3 Chemical requirements The requirements in ISO 8871-1 shall apply I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) 7.4 Biological requirements T he re qu i rements i n I S O 8 71- sh a l l apply Labelling Packed closures which meet the requirements of this document can be labelled with the designation given in Clause © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Annex A (normative) Determination of fragments A.1 Principle T he purp ose of the tes t is to meas ure the relative coring tendencies of different rubb er clos ures T he va lue s ob tai ne d c a n b e s ign i fic a ntly a ffe c te d b y ma ny typ e o f cri mpi ng device, s e a l i ng force, fac tors , s uch a s prior pro ce s s i ng o f the clo s u re s , de s ign o f the s pi ke, its s har pne s s , the a mou nt o f lubric ation o f the s pi ke and the keennes s of the op erator’s s ight I t i s , there fore, ne ce s s a r y to control the s e va ri able s i n order to ob ta i n comp a rable re s u lts I n th i s contex t, a s ub sequent tes t with clos ures of known fragmentation prop er ties can b e included (reference tes t) , i e i n a fi rs t ru n the clo s u re s o f wh ich the fragmentation s hou ld b e eva luate d are te s te d I m me d iately after wards in a second run, clos ures with known fragmentation b ehaviour are tes ted (reference) T his s ubsequent tes ting shou ld b e included from time to time to ens ure appropriate handl ing and fu nc tion i ng o f the te s t s ys tem I f the fragmentation of the reference s amples is found to b e in the range of known res u lts the tes ting is recogni zed as val id A.2 A.2 Apparatus Ten infusion bottles , in accordance with I SO 6-1 (2 infusion bottles are required, should reference testing b e included) A.2 Capping device and aluminium caps in acco rdance with I S O - , and which fit the in fus io n bottles to b e used in the test A.2.3 Membrane filter set A.2 One test spike , in accordance with Annex D T he s ame tes t s pi ke shou ld b e used for al l reference and s ample tes ting A.2 A.3 A.3 Steam autoclave capable to maintain (1 ± ) °C Procedure C o llect a s amp le o f clo s ures s terilizatio n NO TE fo r at (1 ± ) °C , fro m the typ e o r lo t to b e tes ted S ub j ect the clo s ure to s team fo llo wed by drying fo r h at °C I f the clo s u re s i n prac tice a re s ub j e c te d to a s ter i l i z ation pro ce s s o ther th a n s te a m s ter i l i z ation , u s e that s teri l i z ation pro ces s to s teri l i z e the clo s ures and d i s regard B A.3 Prep are in fusion b ottles in acco rdance with I SO 6- , o f any size, filled with % o f the no minal volume o f water Clo se thes e in fus io n bo ttles with s terilized clo sures o f the type to b e tes ted A.3 Fix the closures with aluminium cap s that meet the requirements of I SO 6-3 I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) A.3 D egreas e the tes t s p ike by means o f an ap p ro p riate o rganic s o lvent and dip it into dis tilled water A.3 H o ld the s p ike vertically by hand and p ierce clo s ure N o within the marked area, ho lding the Inspect the spike before use; it shall have its original sharpness and shall not be damaged b o ttle N o firmly in a vertical p o s itio n S hake the b o ttle fo r a few s eco nds and withdraw the s p ike A.3 Repeat A.3.4 and A.3.5 until all 10 closures are pierced once A.3 Remove the tested closures from each bottle Put the content of all the bottles through one memb rane fragments filter E ns ure that no fragments remain in the b o ttles numb er o f C o unt and reco rd the in the filter vis ib le with the naked eye under no rmal co nditio ns , i e at a dis tance b etween eye and filter o f ab o ut cm NO TE A.3 I t i s a s s u me d th at Fo r further fragments identificatio n, determine size and nature A.4 h avi n g a d i a me ter l a rger th a n μm a re vi s ib le to the n a ke d e ye the fragments may be examined with a micro s co p e in o rder to Reference testing If reference testing is performed, prepare test closures with known fragmentation properties as described in A.3 Use the same test spike Re qu a l i fic ation o f the s ys tem i s on l y va l id i f, NO TE same test spike is used A.5 for one s e t o f s a mp le te s ti ng a nd re ference te s ti n g , the Expression of results Report the recorded numbers of fragments per 10 piercings for the closures to be evaluated A.6 Validity Where reference testing is included, the results obtained on the test closures shall be considered i nva l id i f the re s u lts on the known clo s u re s lack s i s tenc y with previou s re s u lts T he re a s on for s uch i ncon s i s tenc y sh a l l b e i nve s tigate d © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Annex B (normative) Determination of spike penetration force B.1 Principle T he purp ose of this tes t is to determine the force required to pierce the clos ure with a s pi ke meeting the requirements o f that specified in Annex D B.2 Apparatus B.2 Ten infusion bottles , in accordance with I SO 6-1 B.2 Capping device and aluminium caps in accordance with ISO 8536-3, and which fit the infusion bottles to b e used in the test B.2 Piercing device which meets the following criteria — A spike, clamped in the device, which can be moved perpendicularly at a speed o f 200 mm/min The force exer ted b ackwards on the s pike during s uch movement is indicated or regis tered in s uch a way that it can be read with an accuracy o f ±2 N — An infus ion b ottle can b e placed in the device in a xial al ignment, al lowing central piercing of the clos ure on this b ottle B.2 Two test spikes , in accordance with Annex D T he s pikes are des ignated as S1 and S2 B.2 B.3 Steam autoclave capable to maintain (1 ± ) °C Procedure B.3 Collect a sample o f 10 closures from the type or lot to be tested Subject the closure to steam sterilization for 30 at (121 ± 2) °C, followed by drying for 16 h at 70 °C NOTE I f the closures in practice are subjected to a sterilization process other than steam sterilization, use that s teri l i z ation pro ces s to s teri l i z e the clo s ures and d i s regard B B.3 Prepare 10 infusion bottles in accordance with ISO 8536-1, o f any size, filled with 50 % o f the nominal volume o f water Close these 10 infusion bottles with sterilized closures o f the type to be tested B.3 Fix the closures with aluminium cap s that meet the requirements of I SO 6-3 B.3 D egrease sp ike S1 with ap propriate organic solvent, exerting the utmost care not to blunt it, and clamp spike S1 in the piercing device I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) B.3 Take the firs t b o ttle and remove the tear- o ff p art o f the s eal s o as to have free acces s to the clo s ure Place the b o ttle in the tes ting device in s uch a way that the clo s ure will b e p er fo rated p erp endicularly and centrally B.3 O p erate the device at a s p eed o f 0 mm/min and regis ter the penetration takes place (see Figure B.1) fo rce B.3 Restore the clamp to its original position and remove the bottle B.3 Repeat B.3.1 to B.3.4 with the next four bottles B.3 Take spike S2 and repeat B.3.1 to B.3.4 exerted immediately b e fo re with the remaining five b o ttles Key force exerted on the spike p force exerted at the moment when the spike pierces the closure movement of the spike F F l Figure B — Model curve B.4 Expression of results Calculate the average values of penetration force for all 10 bottles Calculate the range of the values of penetration force for all 10 bottles B.4.1 B.4.2 If the range is larger than 50 N repeat the experiment If in the repeated test the range of results is still above 50 N, repeat the whole experiment using two new spikes B.4.3 © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Annex C (normative) Spike retention/sealability C.1 Principle The purpose o f this test is to determine the capability o f the stopper to retain a spike and to seal properly around it C.2 Apparatus C.2 Ten infusion bottles , in accordance with I SO 6-1 C.2 Capping device and aluminium caps in accordance with ISO 8536-3, and which fit the infusion bottles to b e used in the test C.2 Test spikes , in accordance with Annex D C.2 Steam autoclave capable to maintain (1 ± ) °C C.3 Procedure Collect a sample o f 10 closures from the type or lot to be tested Subject the closures to steam sterilization for 30 at (121 ± 2) °C, followed by drying for 16 h at 70 °C C.3 NOTE I f the closures in practice are subjected to a sterilization process other than steam sterilization, use that s teri l i z ation pro ces s to s teri l i z e the clo s ures and d i s regard B C.3 Prepare 10 infusion bottles in accordance with ISO 8536-1, o f any size, filled with 50 % o f the nominal volume o f water Close these 10 infusion bottles with sterilized closures o f the type to be tested C.3 Fix the closures with aluminium cap s that meet the requirements of I SO 6-3 C.3 Place the spike, vertically on the centre o f the uncovered part o f an unperforated closure as described in C C.3 Apply a vertical force to the spike Increase this force until complete penetration has occurred or up to the highest manually achievable value C.3 I f a complete penetration has been achieved, then fix the bottle vertically with the bottom end up, and attach a total mass of (0 ,5 ± ,0 ) kg to the spike Leave in this position for h, ob serve and note any signs o f liquid along the spike during this period 10 I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) C.4 Expression of results Report the number of cases where no complete penetration has been achieved, and the number of cases where leakage along the spike during the observation period has occurred C.4.1 Report the number of cases where complete penetration has been achieved, and the number where leakage along the spike during the observation period has occurred C.4.2 C.4.3 Report the number of cases where the spike was not in place after h under stress © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n 11 ISO 85 6-6: 01 6(E) Annex D (normative) Closure piercing device Si nce there i s no pla s tic re ference s pi ke c u rrently avai lable, the u s e o f the s tai n le s s s te el s pi ke i n Figure D.1 i s ne ce s s ar y T he va lue s ob tai ne d may no t correlate with tho s e ob ta i ne d with p las tic s pi ke s Dimensions in millimetres, Surface roughness values in micrometres a) Screwing hook, annealed b) Test spike, S3 400, X5 Cr Ni 1810 (1,43 01) , annealed, see ISO/TS 15510 Figure D.1 — Test spike 12 I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n ISO 85 6-6: 01 6(E) Annex E (informative) Determination of residual moisture E.1 Principle The elastomeric material to be tested is heated in a nitrogen stream in a drying pistol The evaporated water is passed into a titration cell where the amount o f water is determined coulometrically E.2 Apparatus and materials E.2 Karl-Fischer coulometric device E.2 Drying pistol E.2 Nitrogen supply NOTE with a heating system to adjust temperatures between 110 °C and 150 °C with a molecular sieve cartridge Choose nitrogen with a low moisture content E.2 Stainless steel weighing boat E.2 Analytical balance E.2 Reagents E.2 Sodium tartrate, or equivalent E.2 Control solution E.3 E.3 accurate to 0,1 mg as specified in the measurement system manual , with known water content (standard) % (m/m ) water in organic solvent Procedure Apparatus preparation Set up the apparatus as indicated in the instruction manual Adjust the drying pistol to (140 ± 2) °C and flush it with nitrogen at a suitable rate Check the apparatus in particular for — low blank drift, — correct determination of water content of control solution, — constant slope of the cumulative graph water/time when running a blank, and — correct determination of water in sodium tartrate Daily checking is recommended © ISO 2016 – All rights reserved I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n 13 ISO 85 6-6: 01 6(E) E.3 Sample preparation E.3 General Use pincers or wear disposable gloves in handling the closures Maintain the untreated closures in their original packaging and keep treated closures in airtight vessels with a headspace as small as possible H and le clo s ure s at temp erature (2 ± ) ° C and (5 ± 10) % relative hu m id ity E.3 2 Preparing elastomeric material for determination C ol le c t at le a s t 10 clo s u re s and c ut from e ach clo s u re at le as t one s e gment from p erp end ic u lar plane s uch that the s e gment leng th i s approxi mately m m (s e e P ut a l l the s e s egments i n the weigh i ng b o at, ta ki ng s e gments from the top flange a long a Figure E.1) a l l clo s u re s Weigh to an acc u rac y o f 0,1 mg The suitable amount of elastomeric material depends on water content and the determination unit which is used (see E.5) Figure E — Cutting segments from closure E.3 Determination P ut the s egments i nto the d r yi ng pi s tol i m me d iately a fter weigh i ng and s tar t the de term i nation Record the value obtained as a cumulative curve of water content versus time until a constant slope of the curve is reached Double determination is recommended E.4 E.4.1 Calculation and expression of results Extrapolation Figure E.2 s hows s chematic a l ly the c u mu l ative c u r ve a s re corde d du ri ng de term i nation For extrapolation, use the line drawn through the values at, e.g 90 min, 85 min, 80 min, 75 min, 70 Re ad the re s u lts a s m icro gra m s o f water Figure E.2 14 I n tern ati o n al Org an i z ati o n fo r S tan d ard i z ati o n from the graph b y e xtrap olation o f the c u r ve as s hown i n